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Abstract

In the brain of female mammals, including humans, a number of physiological and behavioral
changes occur as a result of sex hormone exposure. Estradiol and progesterone regulate
several brain functions, including learning and memory. Sex hormones contribute to
shape the central nervous system by modulating the formation and turnover of the interconnections
between neurons as well as controlling the function of glial cells. The dynamics of
neuron and glial cells morphology depends on the cytoskeleton and its associated proteins.
Cytoskeletal proteins are necessary to form neuronal dendrites and dendritic spines,
as well as to regulate the diverse functions in astrocytes. The expression pattern
of proteins, such as actin, microtubule-associated protein 2, Tau, and glial fibrillary
acidic protein, changes in a tissue-specific manner in the brain, particularly when
variations in sex hormone levels occur during the estrous or menstrual cycles or pregnancy.
Here, we review the changes in structure and organization of neurons and glial cells
that require the participation of cytoskeletal proteins whose expression and activity
are regulated by estradiol and progesterone.

Motile cells extend a leading edge by assembling a branched network of actin filaments that produces physical force as the polymers grow beneath the plasma membrane. A core set of proteins including actin, Arp2/3 complex, profilin, capping protein, and ADF/cofilin can reconstitute the process in vitro, and mathematical models of the constituent reactions predict the rate of motion. Signaling pathways converging on WASp/Scar proteins regulate the activity of Arp2/3 complex, which mediates the initiation of new filaments as branches on preexisting filaments. After a brief spurt of growth, capping protein terminates the elongation of the filaments. After filaments have aged by hydrolysis of their bound ATP and dissociation of the gamma phosphate, ADF/cofilin proteins promote debranching and depolymerization. Profilin catalyzes the exchange of ADP for ATP, refilling the pool of ATP-actin monomers bound to profilin, ready for elongation.

Spines are neuronal protrusions, each of which receives input typically from one excitatory synapse. They contain neurotransmitter receptors, organelles, and signaling systems essential for synaptic function and plasticity. Numerous brain disorders are associated with abnormal dendritic spines. Spine formation, plasticity, and maintenance depend on synaptic activity and can be modulated by sensory experience. Studies of compartmentalization have shown that spines serve primarily as biochemical, rather than electrical, compartments. In particular, recent work has highlighted that spines are highly specialized compartments for rapid large-amplitude Ca(2+) signals underlying the induction of synaptic plasticity.

The microtubule-associated protein tau is integral to the pathogenesis of Alzheimer's disease (AD), as well as several related disorders, termed tauopathies, in which tau is deposited in affected brain regions. In the tauopathies, pathological tau is in an elevated state of phosphorylation and is aberrantly cleaved. It also exhibits abnormal conformations and becomes aggregated, resulting in neurofibrillary tau pathology. Recent evidence suggests that relatively early disease-associated changes in soluble tau proteins, including phosphorylation, are involved in the induction of neuronal death. Here, we summarize recent developments that suggest new therapeutic strategies to prevent or reduce the progression of pathology in the tauopathies. A list of tau phosphorylation sites identified in the tauopathies and in controls accompanies this review.

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